Immunoregulation by interleukin-12 in MB49.1 tumor-bearing mice: cellular and cytokine-mediated effector mechanisms.
Administration of recombinant murine interleukin (rmIL)-12 to MB49.1 tumor-bearing mice results in dose-dependent regression of the primary tumor and the generation of protective antitumor immunity in the majority of animals. rmIL-12 administration is associated with a marked increase in lymph node cellularity that is predominantly due to the expansion of B220+ B cells as well as CD8+ T cells. Stimulation of lymph node cells from rmIL-12-treated, but not control tumor-bearing mice, with MB49.1 tumor cells in vitro was shown to enhance the secretion of interferon (IFN)-gamma. The magnitude of this in vitro response was dependent on the dose of rmIL-12 administered in vivo and mirrored the change in circulating serum IFN-gamma. Furthermore, at the height of the in vitro response to tumor stimulation, the addition of a neutralizing antibody to murine IL-12 suppressed IFN-gamma production, indicating a role for endogenous IL-12 in this antigen-specific cytokine response. Although studies in SCID mice confirmed that an appropriate T cell response was required for rmIL-12-mediated antitumor activity, in immunocompetent animals early tumor regression was not accompanied by cellular infiltration of the tumor. In contrast, a profound increase in tumor-associated inducible nitric oxide synthase (iNOS) was observed in mice receiving rmIL-12 which preceded T cell infiltration of the tumor which could be detected during the second week of IL-12 treatment. Direct tumor killing through the cytotoxic actions of NO via the iNOS pathway may serve as a way of generating tumor antigen which enables the host to mount a subsequent T cell response against the tumor.
Hunter
S E
SE
Department of Preclinical Research and Development, Genetics Institute, Andover, MA 01810, USA.
Waldburger
K E
KE
Thibodeaux
D K
DK
Schaub
R G
RG
Goldman
S J
SJ
Leonard
J P
JP
D000818:Animals; D007111:Immunity, Cellular; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology
D011994:Recombinant Proteins; D018664:Interleukin-12